Abstract
TTF-1, also known as NKX2-1, is a transcription factor that has indispensable roles in both lung development and physiology. We and others have reported that TTF-1 frequently exhibits high expression with increased copy number in lung adenocarcinomas, and also has a role as a lineage-survival oncogene through transcriptional activation of crucial target genes including ROR1 and LMO3. In the present study, we employed a global proteomic search for proteins that interact with TTF-1 in order to provide a more comprehensive picture of this still enigmatic lineage-survival oncogene. Our results unexpectedly revealed a function independent of its transcriptional activity, as TTF-1 was found to interact with DDB1 and block its binding to CHK1, which in turn attenuated ubiquitylation and subsequent degradation of CHK1. Furthermore, TTF-1 overexpression conferred resistance to cellular conditions under DNA replication stress (RS) and prevented an increase in consequential DNA double-strand breaks, as reflected by attenuated induction of pCHK2 and γH2AX. Our findings suggest that the novel non-transcriptional function of TTF-1 identified in this study may contribute to lung adenocarcinoma development by conferring tolerance to DNA RS, which is known to be inherently elicited by activation of various oncogenes.
| Original language | English |
|---|---|
| Pages (from-to) | 3740-3748 |
| Number of pages | 9 |
| Journal | Oncogene |
| Volume | 36 |
| Issue number | 26 |
| DOIs | |
| Publication status | Published - 29-06-2017 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Genetics
- Cancer Research
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TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas. / Liu, Z.; Yanagisawa, K.; Griesing, S.; Iwai, M.; Kano, K.; Hotta, N.; Kajino, T.; Suzuki, Motoshi; Takahashi, T.
In: Oncogene, Vol. 36, No. 26, 29.06.2017, p. 3740-3748.Research output: Contribution to journal › Article
TY - JOUR
T1 - TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas
AU - Liu, Z.
AU - Yanagisawa, K.
AU - Griesing, S.
AU - Iwai, M.
AU - Kano, K.
AU - Hotta, N.
AU - Kajino, T.
AU - Suzuki, Motoshi
AU - Takahashi, T.
PY - 2017/6/29
Y1 - 2017/6/29
N2 - TTF-1, also known as NKX2-1, is a transcription factor that has indispensable roles in both lung development and physiology. We and others have reported that TTF-1 frequently exhibits high expression with increased copy number in lung adenocarcinomas, and also has a role as a lineage-survival oncogene through transcriptional activation of crucial target genes including ROR1 and LMO3. In the present study, we employed a global proteomic search for proteins that interact with TTF-1 in order to provide a more comprehensive picture of this still enigmatic lineage-survival oncogene. Our results unexpectedly revealed a function independent of its transcriptional activity, as TTF-1 was found to interact with DDB1 and block its binding to CHK1, which in turn attenuated ubiquitylation and subsequent degradation of CHK1. Furthermore, TTF-1 overexpression conferred resistance to cellular conditions under DNA replication stress (RS) and prevented an increase in consequential DNA double-strand breaks, as reflected by attenuated induction of pCHK2 and γH2AX. Our findings suggest that the novel non-transcriptional function of TTF-1 identified in this study may contribute to lung adenocarcinoma development by conferring tolerance to DNA RS, which is known to be inherently elicited by activation of various oncogenes.
AB - TTF-1, also known as NKX2-1, is a transcription factor that has indispensable roles in both lung development and physiology. We and others have reported that TTF-1 frequently exhibits high expression with increased copy number in lung adenocarcinomas, and also has a role as a lineage-survival oncogene through transcriptional activation of crucial target genes including ROR1 and LMO3. In the present study, we employed a global proteomic search for proteins that interact with TTF-1 in order to provide a more comprehensive picture of this still enigmatic lineage-survival oncogene. Our results unexpectedly revealed a function independent of its transcriptional activity, as TTF-1 was found to interact with DDB1 and block its binding to CHK1, which in turn attenuated ubiquitylation and subsequent degradation of CHK1. Furthermore, TTF-1 overexpression conferred resistance to cellular conditions under DNA replication stress (RS) and prevented an increase in consequential DNA double-strand breaks, as reflected by attenuated induction of pCHK2 and γH2AX. Our findings suggest that the novel non-transcriptional function of TTF-1 identified in this study may contribute to lung adenocarcinoma development by conferring tolerance to DNA RS, which is known to be inherently elicited by activation of various oncogenes.
UR - http://www.scopus.com/inward/record.url?scp=85012284361&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85012284361&partnerID=8YFLogxK
U2 - 10.1038/onc.2016.524
DO - 10.1038/onc.2016.524
M3 - Article
C2 - 28192407
AN - SCOPUS:85012284361
VL - 36
SP - 3740
EP - 3748
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 26
ER -